N-acetylcysteine for the prevention of contrast-induced nephropathy: a systematic review and meta-analysis

Liu R, Nair D, Ix J, Moore D H, Bent S

CRD summary

This review investigated whether N-acetylcysteine (NAC) reduces the risk of contrast-induced nephropathy (CIN). The authors concluded that NAC helps prevent declining renal function and CIN. Overall, this was a well-conducted review and the results are likely to be reliable, as long as the limitations of the meta-analysis (pooling of diverse results) are taken into consideration.

MEDLINE (1966 to August 2003), EMBASE (1974 to August 2003) and the Cochrane CENTRAL Register (1996 to August 2003) were searched; the search terms were reported. The reference lists of retrieved articles and reviews were checked, abstracts of conference proceedings (from 2000) of the National Kidney Foundation, American Society of Nephrology, American Heart Association and American College of Cardiology were searched, and experts were consulted.

Study selection

Study designs of evaluations included in the review

Randomised controlled trials (RCTs) were eligible for inclusion.

Specific interventions included in the review

Studies of NAC administered at the time of the contrast agent were eligible for inclusion. NAC was usually given orally, although in one study in the primary analysis it was administered intravenously. The dose of oral NAC ranged from 400 mg twice daily to 1,200 mg once daily, with 600 mg twice daily the most common dose. When given intravenously, the dose was 150 mg/kg.

Participants included in the review

Studies of hospitalised patients receiving a contrast agent were eligible for inclusion. The average age of the participants ranged from 64 to 74 years. Most of the participants had an intra-arterial injection of contrast agent for cardiac catheterisation.

Outcomes assessed in the review

Studies reporting sufficient data to calculate a mean change in creatinine in each group, or the proportion of patients developing CIN, at 48 hours were eligible for inclusion. The primary outcome measure was the mean change in creatinine. Secondary outcomes were the development of CIN and the requirement of dialysis. Most studies defined CIN as either a 25% or a 0.5 mg/dL increase in serum creatinine.

How were decisions on the relevance of primary studies made?

Two reviewers independently assessed the relevance of studies for inclusion in the review. A third reviewer resolved any disagreements.

Assessment of study quality

Study quality was assessed in terms of randomisation, allocation concealment, and blinding of the patients and carers. Studies complying with two or more criteria were deemed high quality. Two reviewers independently assessed validity. A third reviewer resolved any disagreements.

Data extraction

Two reviewers independently extracted the data for the review, using a standardised form. A third reviewer resolved any disagreements. The differences in the mean change in creatinine and 95% confidence intervals (CIs) between patients treated with NAC and controls, and the relative risk (RR) and 95% CI of developing CIN or requiring dialysis, were calculated for each study.

Methods of synthesis

How were the studies combined?

The pooled weighted mean differences (WMD) and 95% CIs for changes in creatinine, and pooled RR and 95% CI for developing CIN or requiring dialysis, were calculated using random-effects meta-analyses. Publication bias was investigated using the Begg and Mazumdar rank correlation test and Egger's regression asymmetry test.

How were differences between studies investigated?

Heterogeneity was assessed using the chi-squared statistic. Forest plots were presented to allow visual inspection of the results for heterogeneity. Subgroup analyses were carried out to investigate the effect of the baseline level of creatinine, dose of NAC, volume of contrast used, hydration fluid used and the proportion of diabetics included. Sensitivity analyses were conducted to determine whether features of study design explained the heterogeneity observed.

Results of the review

Nine RCTs (n=1,028) were included in the review.

In terms of quality, five studies scored 0, two studies scored 1 and two studies scored 2, out of a maximum of 4.

There was a statistically significant benefit of NAC in relation to the mean change in creatinine at 48 hours (8 RCTs), with a WMD of -0.27 mg/dL (95% CI: -0.43, -0.11). When only placebo-controlled RCTs (6 RCTs) were analysed, the WMD was -0.39 (95% CI: -0.56, -0.22). A subgroup analysis of patients undergoing cardiac catheterisation showed a statistically significant benefit of NAC (8 RCTs), with a WMD of -0.22 mg/dL (95% CI: -0.38, -0.06). There was statistically significant heterogeneity between the studies in these analyses (P<0.05).

There was a statistically significant benefit of NAC regarding the development of CIN (9 RCTs), with an RR of 0.42 (95% CI: 0.24, 0.75). A subgroup analysis of patients undergoing cardiac catheterisation showed a statistically significant benefit of NAC (8 RCTs), with an RR of developing CIN of 0.46 (95% CI: 0.26, 0.82). There was statistically significant heterogeneity between the studies in these analyses (P<0.05).

There was no statistically significant benefit of NAC regarding the requirement of dialysis (7 RCTs), with an RR of 0.64 (95% CI: 0.15, 2.78).

The authors reported that there was no evidence of publication bias for the outcome of change in creatinine. There was evidence of publication bias for the outcome of CIN when based on RR, but not risk difference.

Authors' conclusions

NAC helped to prevent declining renal function and CIN.

CRD commentary

The research question was clear in terms of the intervention, population, outcomes and study design. Several relevant sources were searched, and the authors investigated the possibility of publication bias. Methods were used to reduce the potential for error and bias throughout the review process. Study quality was assessed, and referred to in the narrative and used to investigate heterogeneity. Relevant measures of effect were calculated. There were discrepancies in the pooled values reported for the RR of developing CIN between the text and forest plots. As the authors indicated, heterogeneity between studies limits the value of the summary statistics of the meta-analysis, and the appropriateness of pooling such data may be questionable. Overall, this was a well-conducted review and the results are likely to be reliable, as long as the limitations of the meta-analysis are taken into consideration.

Implications of the review for practice and research

Practice: The authors stated that considering the apparent low cost of NAC, and the potential benefits, it may be argued that NAC should be recommended for widespread use prior to contrast administration in all patients.

Research: The authors recommended that RCTs to assess the effect of NAC on long-term outcomes and overall costs are required. Such RCTs should use a standardised dose or regimen of NAC, fluid hydration, contrast and placebo, and measure renal failure, rates of dialysis, death, major cardiac events and length of hospitalisation as outcomes. They went on to recommend that the baseline characteristics of populations should be clearly defined.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.